A scalable and expedient route to 1-Aza[6]helicene derivatives and its subsequent application to a chiral-relay asymmetric strategy

Article abstract of DOI:10.1021/ol400493x

A rapid route to diversely functionalized 1-aza[6]helicenes has been achieved via the development of a copper-mediated cross-coupling reaction, followed by PtCl₄-catalyzed cycloisomerization. Not only does this method allow access to these func

Full text of DOI:10.1021/ol400493x

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
A Scalable and Expedient Route to
1‑Aza[6]helicene Derivatives and Its
Subsequent Application to a Chiral-Relay
Asymmetric Strategy
Marko Weimar, Rosenildo Correa da Costa, Fu-Howe Lee, and Matthew J. Fuchter*
Department of Chemistry, Imperial College London, London SW7 2AZ,
United Kingdom
m.fuchter@imperial.ac.uk
Received February 22, 2013
ABSTRACT
A rapid route to diversely functionalized 1-aza[6]helicenes has been achieved via the development of a copper-mediated cross-coupling reaction,
followed by PtCl4-catalyzed cycloisomerization. Not only does this method allow access to these functionally important molecules on gram scale,
but this strategy is also suitable for relaying the axial chirality of a key intermediate to the helicity of the product.
Interest in the inherently chiral aromatics known as
the helicenes continues to expand due to their fascinat-
ing helical, and therefore chiral, topology coupled with
their fully conjugated aromatic structure.1 These chiral
aromatics promise to have wide-ranging impact, with
preliminary studies already reported in the fields of
catalysis,2ꢀ7 nonlinear optics,8 electrooptical switches,9
and molecular recognition,10ꢀ13 among others. Azaheli-
cenes (such as 4) have been a particularly exciting target
class of helicenes recently for chemical synthesis,1ꢀ3,14
exhibiting fascinating coordination chemistry,13ꢀ16 self-
assembly potential,17 and interesting photophysics.18 We
(1) For helicene reviews, see: (a) Martin, R. H. Angew. Chem., Int. Ed.
Engl. 1974, 13, 649. (b) Urbano, A. Angew. Chem., Int. Ed. 2003, 42, 3986. (c)
Collins, S. K.; Vachon, M. P. Org. Biomol. Chem. 2006, 4, 2518. (d) Chen, J.;
(8) Verbiest, T.; Elshocht, S. V.; Kauranen, M.; Hellemans, L.;
Snauwaert, J.; Nuckolls, C.; Katz, T. J.; Persoons, A. Science
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Katz, T. J. Chem. Mater. 2002, 14, 773.
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Tanaka, K. J. Am. Chem. Soc. 2004, 126, 6566.
(12) Xu, Y.; Yamazaki, S.; Osuga, H.; Sugiyama, H. Nucleic Acids
Symp. Ser. 2006, 50, 183.
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Takenaka, N. Chem.;Eur. J. 2009, 15, 7268. (e) Stary, I.; Stara, I. G.;
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Alexandrova, Z.; Sehnal, P.; Teply, F.; Saman, D.; Rulısek, L. Pure Appl.
Chem. 2006, 79, 495. (f) Dumitrascu, F.; Dumitrescu, D. G.; Aron, I.
ARKIVOC 2010, 1, 1. (g) Shen, Y.; Chen, C.-F. Chem. Rev. 2012, 112, 1463.
(2) For example uses of azahelicenes in organocatalysis, see:
(a) Takenaka, N.; Sarangthem, R. S.; Captain, B. Angew. Chem., Int. Ed.
2008, 47, 9708. (b) Chen, J.; Takenaka, N. Chem.;Eur. J. 2009, 15, 7268. (c)
Takenaka, N.; Chen, J.; Captain, B.; Sarangthem, R. S.; Chandrakumar, A.
J. Am. Chem. Soc. 2010, 132, 4536. (d) Chen, J.; Captain, B.; Takenaka, N.
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M.; Krossing, I. Dalton Trans. 2012, 41, 8238. (b) Fuchter, M. J.; Weimar, M.;
(3) (a) Crittall, M. R.; Rzepa, H. S.; Carbery, D. R. Org. Lett. 2011,
13, 1250. (b) Crittall, M. R.; Fairhurst, N. W. G.; Carbery, D. R. Chem.
Commun. 2012, 48, 11181.
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10.1021/ol400493x
XXXX American Chemical Society

have recently demonstrated the high potential of this class
in materials science, using enantiopure dopant quantities
of 1-aza[6]helicene (4) to induce circularly polarized (CP)
electroluminescence from an achiral light-emitting poly-
mer19 and fabricating organic phototransistors based on 4
that can reversibly detect CP light.20 Furthermore, there
has been much interest in exploiting the chiral scaffold of
azahelicenes in asymmetric organocatalysis (Figure 1).
Takenaka and co-workers have reported 1-azahelicene
derivatives 1 and 2 as helical organocatalysts2aꢀd for en-
antioselective ring-opening of meso-epoxides, the addition
of dihydroindoles to nitroalkenes, and the propargylation
To enable a more rapid synthesis of 1-aza[6]helicene (4),
we envisaged disconnecting to key biaryl species 6 via a
cycloisomerization reaction (Figure 1b). Cycloisomeriza-
tion has been shown to be an applicable synthetic strategy
to prepare carbohelicenes,22 although very limited success
has been obtained when using this chemistry on systems
bearing π-deficient pyridine moieties.23 Indeed, in general,
only electron-rich systems have been reported as suitable
substrates,24 thus allowing significant scope for improve-
ment. Further disconnection of the arylꢀaryl bond in 6
would lead to readily available benzo[h]quinoline derivatives
7 and functionalized naphthalenes 8. While we suspected the
formation of such a hindered biaryl bond in 6 would be
challenging, the likely high barrier to rotation about the
arylꢀaryl bond was seen as an opportunity to isolate axial
stereoisomers of 6, the stereochemistry of which could
potentially be selectively relayed to the helical product.
We commenced our attempts to construct the crucial
biaryl bond in 6 by using either CꢀH arylation chemistry25
or conventional metal-catalyzed cross-coupling methodol-
ogy; however, we found that the vast majority of processes
attempted failed to deliver the hindered biaryl product.
With 10-bromobenzo[h]quinoline 7a,26 alkyne 9,27 and
boronic acid 10 in hand, we instead decided to investigate
the use of copper salts.28 With a stoichiometric amount of
CuI, the cross coupling of bromide 7a with boronic acid 10
in THF and in the presence of CsF afforded a mixture of 11
and 6 in moderate yield, whereby the TMS group had been
partially cleaved (Scheme 1). Following optimization, we
found that the cuprate of 9, formed in situ via lithiumꢀ
bromide exchange and transmetalation with CuI, reacted
with 7a to give 11 in high yield (79%).
ꢀ
ꢀ
of aldehydes with allenyltrichlorosilane. Stary, Stara, and
co-workers also used 1-aza-(4) and 2-aza[6]helicene (5) as
organocatalysts in the asymmetric acyl-transfer reac-
tions of rac-1-phenylethanol.2e Similarly, kinetic resolu-
tion chemistry has been reported by Carbery and co-
workers using a helicenoidal DMAP analogue 3, with
good to excellent levels of selectivity (S e 116).3
Figure 1. (a) Azahelicene or helicenoid chiral organocatalysts;
(b) retrosynthetic analysis of target helicene 4.
Scheme 1. Synthesis of Key Intermediate 6
Despite these exciting preliminary applications, one of the
key limitations for azahelicene study is access to significant
quantities of material. Only limited reports have concerned
the synthesis of helicene enantiomers on a >1 g scale,21 and
the current routes reported toward 1-aza[6]helicenes (4) have
several drawbacks. For example, the Takenaka route2a,b
involves seven linear steps to assemble three fragments, all of
which are noncommercially available, and it uses significant
amounts of hexamethylditin to mediate two arylꢀaryl bond
ꢀ
formation steps. Alternatively, the route developed by Stary,
Stara, and co-workers14 comprises eight linear steps starting
ꢀ
ꢀ
ꢁ
ꢀ
ꢁ ꢀ
(22) Storch, J.; Sykora, J.; Cermak, J.; Karban, J.; Cısarova, I.;
from two noncommercial fragments and requires 30 equiv
of MnO2 in a final oxidation step. In both cases, the
enantiopure products were obtained by semipreparative
chiral HPLC or crystallization of diastereomeric salts.
ꢁ
ꢁ
Ruzicka, A. J. Org. Chem. 2009, 74, 3090.
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(23) Storch, J.; Cermak, J.; Karban, J.; Cısarova, I.; Sykora, J. J. Org.
Chem. 2010, 75, 3137.
(24) For reviews on cycloisomerization reactions, see: (a) Furstner, A.;
ꢀ
€
Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410. (b) Kirsch, S. F. Synthesis
2008, 3183. (c) Belmont, P.; Parker, E. Eur. J. Org. Chem. 2009, 6075.
(25) For reviews discussing CꢀH arylation, see: (a) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (b) McGlacken, G. P.;
Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447. (c) Chen, X.; Engle, K. M.;
Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (d)
Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009,
48, 9792. (e) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (f) Cho,
S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068.
(26) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,
126, 2300.
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Caronna, T.; Tubino, R.; Meinardi, F. J. Phys. Chem. A 2006, 110, 11018.
(19) Yang, Y.; Correa da Costa, R.; Campbell, A. J.; Fuchter, M. J.
Adv. Mater. 2013, in press. DOI: 10.1002/adma.201204961
(20) Yang, Y.; Correa da Costa, R.; Fuchter, M. J.; Campbell, A. J.
2013, submitted.
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(21) Vavra, J.; Severa, L.; Svec, P.; Cısarova, I.; Koval, D.; Sazelova,
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Org. Lett., Vol. XX, No. XX, XXXX

With key biaryl 11 in hand, the cycloisomerization
of deprotected alkyne 6 was investigated. As suspected,
this was highly challenging, with well-established π-Lewis
acids, such as PtCl2, InCl3, and GaCl3 in addition to other
gold and ruthenium complexes, failing to give any conver-
sion. This was shown to be due to the presence of the
pyridine functionality (see the Supporting Information).
Since sporadic reports have emerged demonstrating PtCl4
to be more effective than PtCl2 in similar reactions,29 we
examined this catalyst. Storch et al. reported the successful
cycloisomerization of a single related substrate,23 using 0.05
equiv of PtCl4 and 0.05 equiv of InCl3 at 90 °C in toluene,
although this chemistry had poor substrate scope. In our
hands, even with 0.5 equiv of each Lewis acid, only traces
of product were obtained when using substrate 6. Raising
the reaction temperature to 120 °C in DCE, however, gave a
much improved conversion. At this increased temperature
we found InCl3 to be unnecessary, and we were able to lower
the catalyst loading of PtCl4. Indeed, when the reaction was
carried out in the presence of 10 mol % of PtCl4 at 120 °C,
the helicene product 4 was obtained in up to 65% yield
(Scheme 2). We found this procedure could be further
telescoped by employing substrate 11 in the cycloisome-
rization reaction directly. The TMS group was cleaved in
situ and product 4 isolated in comparable yield.
commercially available 1-bromo-2-naphthol. Furthermore,
this chemistry was scalable, allowing us to easily prepare 1 g
of 4 in a single run.
Scheme 3. Synthesis of Azahelicene Analogues
While carrying out additional optimization studies, we
found that certain diene additives30 were beneficial for the
reaction, giving a significant rate enhancement. In a survey
of dienes, (racemic) R-phellandrene was found to be the
optimum additive. Using racemic R-phellandrene as an
additive, the reaction temperature could be reduced to
80 °C giving 4 in comparable yield under otherwise iden-
tical conditions (Scheme 2).
With our novel synthesis in hand, we prepared a range
of substituted aza[6]helicenes (Scheme 3). In light of our
previous demonstration of these helicenes in plastic elec-
tronic devices,19,20 such derivatives offer a highly useful
means to tune the requisite energy levels of a given
azahelicene. Indeed, calculation of the HOMO and
LUMO energy levels of helicene 4 and a 15-dimethylamino
derivative 22 at the B3LYP/6-31þG(d,p) level of theory
demonstrates that addition of an electron-donating amino
substituent results in a drop in ionization potential by
0.49 eV, through alteration of the HOMO energy level,
with little effect on the LUMO. This can be explained by
inspection of the contribution of this substituent to the
HOMO of 22 (Figure 2).
Scheme 2. Optimized Cycloisomerization
Bromoalkynes 1227 were coupled with bromobenzo-
[h]quinoline 7a in good yield using a stoichiometric
amount of CuI (Scheme 3). The TMS group was removed
with TBAF, and the free alkynes 14 were subjected to the
developed cycloisomerization conditions. The methyl
ethers 15 were cleaved with BCl3/TBAI, and the liberated
hydroxyl groups converted to the corresponding tri-
flates 17 in order to introduce further functionality via a
variety of transition-metal-catalyzed processes. The cross-
coupling reaction of triflate 17a with boronic acid 18
proceeded without issue to give helicene 19 in good yield
Overall, 1-aza[6]helicene 4 was synthesized in four linear
steps (or five steps overall) in a yield of ∼35% from
(27) Kamikawa, T.; Hayashi, T. J. Org. Chem. 1998, 63, 8922.
(28) (a) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004,
ꢀ
248, 2337. (b) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. Rev. 2002, 102, 1359.
(29) For examples, see: (a) Pastine, S. J.; Youn, S. W.; Sames, D. Org.
Lett. 2003, 5, 1055. (b) Hiroya, K.; Matsumoto, S.; Ashikawa, M.;
Ogiwara, K.; Sakamoto, T. Org. Lett. 2006, 8, 5349. (c) Li, G.; Huang,
X.; Zhang, L. Angew. Chem., Int. Ed. 2008, 47, 346. (d) Tobisu, M.;
Nakai, H.; Chatani, N. J. Org. Chem. 2009, 74, 5471.
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(30) Klahn, P.; Duschek, A.; Liebert, C.; Kirsch, S. F. Org. Lett.
2012, 14, 1250.
Org. Lett., Vol. XX, No. XX, XXXX
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Information) as have been done previously.31 We believe
this is the first example of axial to helical chiral relay using
such cycloisomerization chemistry. The apparent loss of
stereochemical information is likely within error of the
measurement, since product racemization14 would not be
significant under these conditions (see the Supporting
Information). The high-fidelity transfer of stereochemical
information from biaryl 6 to helicene 4 opens up the
possibility of an enantioselective synthesis of azahelicenes
using this strategy in the future via enantioselective syn-
thesis of biaryl 6.32 Indeed, asymmetric transition-metal-
catalyzed processes to prepare enantioenriched axially
chiral biaryls are beginning to emerge.33
In conclusion, we have developed a rapid and robust
strategy to prepare functionalized 1-aza[6]helicenes. In
light of the high interest of these particular helicenes in
catalysis, coordination chemistry, self-assembly, and ma-
terials science, we believe our route should enable material
for further in-depth study. Furthermore, it is likely
that a number of the derivatives prepared have interest-
ing organocatalytic properties. Indeed, inspection of
15-pyrrolidine-substituted product 20a and 14-pyrrolidine-
substituted product 20b reveals that in the former case the
amino substituent is fully conjugated with the pyrido
nitrogen, whereas it is not in the latter case (Scheme 4). As
such, one could expect interesting differences in catalysis
stemming from the study of such fully helically conjugated
DMAP analogues. These and related studies are ongoing
in our laboratories and will be reported in due course.
Figure 2. Comparison of the HOMOs of azahelicenes 4 and 22.
(90%). Furthermore, the installation of the pyrrolidine
unit using BuchwaldꢀHartwig chemistry or the introduc-
tion of carbonyl functionality via a Heck reaction were
equally possible, giving helicenes 20a/20b or 21 respectively.
With a highly efficient racemic synthetic route in hand,
we next considered the potential for this strategy to be
carried out asymmetrically, in order to isolate enantioen-
riched products directly. We found highly hindered biaryl
6 could be isolated as axially chiral atropisomers using
semipreparative chiral HPLC. These enantiomers were
highly stable to racemization: Heating single enantiomer
Ra-6 to 120 °C overnight in 1-nonanol resulted in no
erosion of enantiopurity. In light of this, we felt there
was significant scope to relay the stereochemical informa-
tion from the chiral axis of alkyne 6 to the helicity of
helicene 4, using the developed methodology. Samples of
enantiomer Ra-6 (92% ee) and enantiomer Sa-6 (94% ee)
weresubjectedtotheoptimized cycloisomerization. To our
delight, there was excellent relay of stereochemical infor-
mation, with the helicene products M-4 and P-4 isolated in
90% and 92% ee, respectively. Assignments of absolute
stereochemistry were made by comparison of experimen-
tally obtained electronic circular dichroism (ECD) spectra
with theoretically predicted ones (see the Supporting
Scheme 4. Helical DMAP Analogues
Acknowledgment. We thank the Engineering and Phy-
sical Sciences Research Council for a Bright Ideas Award
(to M.J.F., Grant No. EP/I014535/1) and the Leverhulme
Trust (Grant No. F/07058/BG) for funding this work.
(31) Cherblanc, F.; Lo, Y.-P.; De Gussem, E.; Alcazar-Fuoli, L.;
Bignell, E.; He, Y.; Chapman-Rothe, N.; Bultinck, P.; Herrebout, W. A.;
Brown, R.; Rzepa, H. S.; Fuchter, M. J. Chem.;Eur. J. 2011, 17, 11868.
(32) In a preliminary survey we found the addition of a stoichiometric
amount of the chiral ligand MonoPhos to the developed copper
mediated conversion of 7a to give 11 gave a low, but reproducible, 5%
ee of the product. Further optimization studies are ongoing.
(33) (a) Shen, X.; Jones, G. O.; Watson, D. A.; Bhayana, B.;
Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 11278and references cited
therein. (b) Yamamoto, T.; Akai, Y.; Nagata, Y.; Suginome, M. Angew.
Chem., Int. Ed. 2011, 50, 8844.
Supporting Information Available. Full experimental
proceedures, compound characterization, reaction opti-
mization, and racemization barriers.This material is
available free of charge via the Internet at http://pubs.
acs.org.
The authors declare no competing financial interest.
D
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